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(11) | EP 0 118 875 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | 6-(Hydroxyalkyl)-2-(heteroarylalkylthio)-penems, pharmaceutical compositions containing them, and processes for their preparation |
| (57) Compounds of the general formula
In which G is hydroxyloweralkyl; R1 is chosen from various substituents; n is 1 to 4; Q is the group
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[0001] This invention relates to novel 6-(hydroxyalkyl)-2-(heteroarylalkylthio)penems having the general formula:
wherein G is hydroxyloweralkyl,
Q is the group
wherein
each X is
or =N-, with the proviso that at least
one X is
R is hydrogen, loweralkyl, aminoloweralkyl, mono- and di-loweralkylaminoloweralkyl, carboxyloweralkyl, sulfoalkyl, hydroxyalkyl, cyano, hydroxy, amino, mono- and di-loweralkylamino, alkylsulfonate, sulfamyl, halogeno, hydroxyliminoloweralkyl, loweralkoxyimino-, loweralkyl, carboxy, carbamyl, mono- or di-loweralkylcarbamyl, nitro, carbamyloxy, ureidoloweralkyl, or carbamyl- hydrazoloweralkyl; or two R aroups, together with the carbon atoms to which they are attached, form a fused aromatic ring;
R1 is hydrogen, loweralkyl, carboxy, carbamyl, cyano, hydroxy, amino, loweralkylthio,
fluoro, loweralkoxy, loweralkanoyloxy, or loweralkyl substituted by imidazolyl(which
may be substituted by a group defined by R or by ureido), hydroxy, cyano, halogen,
loweralkoxy, carbamyloxy, carboxy, carbamyl, loweralkylcarbonyl, sulfo, sulfamyl,
loweralkylsulfonyl, loweralkoxysulfo- nyl,loweralkoxycarbonyl, hydroxyloweralkylcarbonyl
or hydroxyloweralkylsulfonyl, with the proviso that when R is attached to a carbon
atom adjacent either to the sulphur atom connected to the 2-position of the penem
ring or the nitrogen atom by which the group Q is connected to the side chain
then such R1 cannot be hydroxy, amino or fluoro;
n is 1 to 4;
and
the pharmaceutically acceptable salts and esters thereof, in racemic or optically active form.
[0002] Preferred compounds of formula I are those wherein the group Q i.s chosen from the following groups which may be unsubstituted or substituted; pyrrolyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, 4,1,2-triazolyl, 1,2,3-triazolyl, 2,1,3-triazolyl, 1,2,3,4-tetrazolyl and 2,1,3,4-tetrazolyl. The substituents, if present, are 1 to 4 "R" groups. Most preferred are compounds of formula I wherein the group Q is imidazolyl or a triazolyl group.
[0003] A preferred fused aromatic ring which may be contained in Q is a six-membered aromatic ring which may contain up to 3 nitrogen atoms as ring heteroatoms. Typical examples of groups Q containing such a fused aromatic ring are indolyl, isoindolyl, isoindazolyl, benzimidazolyl, indazolyl, 1,2,3-benzotriazolyl, 2,1,3-benzotriazolyl, 4,5,6 or 7-azaindolyl, 4,5,6 or 7-azabenzimidazolyl, 4,5,6 or 7-azabenzopyrazolyl, l,pyrazolo-[3,4-d]-pyrimidinyl, 2-pyroazolo-[4,3-c]-pyridinyl, 3-v-triazolo-[4,5-b]-pyridinyl; 1-pyrazolo-[3,4-b]-pyrazinyl, 2-v-triazolo-[4,5-b]-pyrazinyl, and 1,3,4,6-benzotetrazolyl.
[0006] Also preferred are compounds of formula I wherein n is 2 to 4; most preferred are those compounds wherein n is 2.
[0008] The term "loweralkyl" as used herein means alkyl groups of 1 to 6 carbon atoms and includes methyl, ethyl, propyl, butyl, pentyl and hexyl and the corresponding branched chain isomers thereof. Similarly, "loweralkoxy" means straight or branched alkoxy groups having 1 to 6 carbon atomra, e.g., methoxy, ethoxy, propoxy and butoxy, and "loweralkanoyloxy" means straight or branched chain alkanoyloxy groups of 1 to 6 carbon atoms, e.g. acetoxy, propionoxy, and butyryloxy.
[0009] Compounds of the present invention possess a number of asymmetric carbon atoms, indicated in the partial formula II below at the 5, 6, and possibly in the 2' to 5'-position carbon atoms. Also where G is hydroxy loweralkyl other than hydroxymethyl the carbon atom to which the hydroxy group is attached will be asymmetric.
Where G is 1-hydroxyethyl the compounds of the invention preferably possess 5R,6S,8R or 5R,6R,8S stereochemistry at the indicated chiral atoms. The preferred absolute stereochemistry for such compounds of the present invention at those positions is 5R,6S,8R.
[0010] Compounds of formula I wherein R is other than hydrogen will have asymmetric carbon atom(s) as shown in formula II at the 2' to 5' positions.
[0011] The present invention contemplates compounds of formula I in stereospecific form or as mixtures of such stereoisomers.
[0012] As used herein, "pharmaceutically acceptable salts" preferably means alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium, magnesium and aluminum salts; amine salts formed from a wide variety of suitable organic amines, i.e., aliphatic, cycloaliphatic, (cyloaliphatic)aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, or heterocyclic bases, e.g., salts derived from triethylamine, 2-hydroxyethylamine, di-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, 4-aminobenzoic acid-2-diethylaminoethyl ester, 1-ethylpiperidine, bicyclohexylamine, N,N'-dibenzylethylenediamine, pyridine, collidine,quinoline, procaine, dibenzylamine, 1-ephenamine and N-alkylpiperidine; or acid addition salts formed from mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric or sulfuric acids, or formed from organic carboxylic or sulfonic acids such as trifluoroacetic, para-toluene sulfonic, maleic, acetic, citric, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic and malic acids.
[0013] Compounds of this invention which contain a 3-carboxylic group and a basic group (which may be an Ri group e.g. an amine), or the group Q (especially a group Q containing two nitrogen atoms) may form an inner salt i.e. a zwitterion.
[0014] "Pharmaceutically acceptable esters" means physiologically cleavable esters, i.e., metabolizable esters known in the penicillin, cephalosporin and penem arts to be easily cleaved within the body to the parent acid. Examples of groups forming such esters are indanyl, phthalidyl, methoxymethyl, glycyloxymethyl, phenylglycyloxy- methyl, thienylglycyloxymethyl, acetoxymethyl and pivaloyloxymethyl.
[0015] When tested in standardized microbiological assay, the compounds of this invention are active against such gram-positive organisms as Staphylococcus epidermis and Bacillus subtilis, and such gram-negative organisms as E. coli and Salmonella, at test levels of 0.01 to 1.0 micrograms/ml. Additionally, they show activity against organisms which produce beta-lactamases, e.g. penicil- linase and cephalosperinase, indicating a stability toward these enzymes. For instance, 5R,6S,8R-2-[2-(imidazol-1-yl)-ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylic acid is active against Enterobacter 72012502 at a test level of 0.250 microgram/ml. When tested against E. coli 74081501 TEM-1 (a beta-lactamase producing organism) the compound exhibits activity at 0.031 microgram/ml. When tested against over sixty organisms, the mean test level against gram-negative organisms was 0.135 microgram/ml and against gram-positive organisms was 0.061 microgram/ml.
[0017] As antibacterial agents, the compounds of this invention are conventionally formulated for oral, parenteral, topical and transdermal use. Thus, this invention includes within its scope pharmaceutical compositions comprising the compounds of this invention in admixture with a pharmaceutically acceptable carrier therefor. In the foregoing compositions, the compounds of this invention can be used as the sole active antibacterial agent or in combination with other antibacterial agents and/or enzyme inhibitors.
[0018] For oral administration, the compounds of this invention are typically formulated in the form of tablets, capsules, elixirs, or the like. For parenteral administration they may be formulated into solutions or suspensions.
[0019] The dosage of a compound of this invention which is administered will be dependent on the judgment of the attending clinician taking into account a variety of factors, i.e., the age and weight of the individual being treated, the mode of administration, and the type and severity of the-bacterial infection being prevented or reduced and the potency of the specific compound administered. Typically, the dosage administered per day will be in the range of from about 1 to 250 mg/kg and preferably from about 5 to 20 mg/kg in divided dosages.
[0020] Typically, the dosage will be administered in dosage units containing convenient amounts, for example, 125, 250 or 500 mg of active ingredient combined with a suitable physiologically acceptable carrier or diluent.
[0021] According to another aspect of the present invention a process for preparing a compound of formula I as defined above or its salts or esters, is characterized in that:
A) a compound of formula [IX(a), IX(b)]
in which G is as defined above, is transformed into a compound of formula I by introducing
the group
(in which Q, n and R1 are as previously defined) by known conventional methods;
B) Reaction of a compound of the general formula XI
in which G is as defined above and R is an organic group, with a compound of general
formula XII
in which Q, n and R' are as previously defined, or with a reactive derivative thereof,
wherein the group R is different from the group
by which it is replaced,
C) intramolecular cyclisation of a compound having the general formula XIII
in which G, n, R1 and Q are as defined above and Z is oxygen or sulphur, in the presence of a trivalent
organophosphorous compound;
D) for the preparation of a compound of formula I in which at least one R1 is cyano or fluoro, converting at least one hydroxyl group representing R1 in an compound of formula I into the cyano or fluoro group;
wherein in the processes A, B, C or D, any functional groups are protected if necessary
or desired,
the process A, B, C , or D, being followed by removal of any protecting groups, before or after any desired separation of a stereoisomer, and isolation of the resulting penem compound of formula I as the free acid, pharmaceutically acceptable salt or pharmaceutically acceptable ester.
Process A):
[0022] The transformation of tautomer [IX(a), IX(b)] to a compound of formula I is preferably carried out using a process similar to one or other of the transformation processes described in European Patent Application No. 83111615.7, that is by:
(i) reaction with a compound of formula X
in which Q, R1 and n are as defined above and Zlis a group leaving under the conditions of the reaction, e.g. activated hyd: halogen,
CH3SO2-O0-, O--P+(C6H5)3, or the group CF3SO3-. Suitable halogens are chlorine, bromine and iodine.
[0023] Such reaction is preferably carried out in an organic solvent such as tetrahydrofuran in an inert atmosphere at a temperature typically between -5°C and 30°C. The reaction will generally be carried out in the presence of a base or acid acceptor, e.g. an inorganic carbonate, and the reaction will be generally complete within 1 to 3 hours.
[0024] (ii) Reaction with a 1,2-epoxy compound of the formula X'
in which Q and RI are as defined above and n' is 0 to 2.
[0025] This reaction can be used for producing compounds of formula I in which R1 group attached to the second carbon atom from the sulphur atom connected to the 2-position of the penem ring is hydroxy, i.e. compounds having the partial structure
[0026] Such reaction can be carried out by combining the tautomer and the compound of formula X' at, or about at room temperature, usually in a suitable inert solvent such as dimethylformamide.
[0027] Procedure B) involving sulfoxide replacement can be carried out, usually in an inert solvent, e.g. dichloromethane or THF. The reaction temperature is usually in the range of 0°C to -70°C.
[0028] When the thiol compound XII is itself used, the reaction is generally carried out in the presence of a base, e.g. an organic base e.g. diisopropylethylamine or triethylamine, or an inorganic base, e.g. potassium hydroxide or sodium methoxide.
[0029] Alternatively a reactive derivative, e.g. an alkali metal salt, preferably sodium or potassium may be used.
[0030] The sulfoxides of formula XI can be obtained by treating a compound of the formula XI'.
in which G and R are as defined above, with a mild oxidizing agent e.g. peroxybenzoic acid in an inert solvent, e.g. dichloromethane,at between -30°C and 20°C e.g. 0°C to 5°C.
[0031] A compound of formula XI' can be prepared by the method disclosed in our European Patent Specification Publication No. 13662 or by the methods disclosed herein.
[0032] Procedure C), involving cyclisation of the compound of formula XIII will generally be carried out analogously to the process described in our European Patent Application, Publication No. 58317.
[0033] Thus it is usually carried out in an inert solvent, for example an aromatic hydrocarbon, e.g. toluene, benzene, aliphatic ethers e.g. diethyl ethers and dipropyl ether, cyclic ethers e.g. dioxane and tetrahydrofuran and halogenated hydrocarbons e.g. methylene chloride and chloroform.
[0034] In general the oyclization reaction is conducted at temperatures in the range from 20°C to 80°C, usually from 40°C to 60°C for a period of from 6 to 24 hours.
[0035] Suitable trivalent organophosphorous compounds are cyclic and/or acyclic trialkylphosphites, triarylphosphites and mixed arylalkylphosphites or phosphoramides. The preferred trivalent organophosphorous compound is a trialkylphosphite; most preferred is triethylphosphite.
[0036] Process D can be carried out by methods known in the art for replacing the hydroxy of hydroxyalkyl groups with fluoro or cyano.
[0037] A convenient general procedure is to react the hydroxy side chain with dialkylazido carboxylate (DAC) and triphenyl phosphine (TPP) to convert the hydroxy to a leaving group, which can then be displaced with fluoro or cyano anion. For example, a suitably protected penem in solution in a suitable inert solvent such as methylene chloride can be added to the DAC and TPP reagents under cooling e.g. -30oC to -10°C preferably -20°C. A fluoro or cyano ion source can then be added, for example sodium or potassium cyanide, or diphenoxycyanophosphine, or a solution of hydrogen fluoride in pyridine.
[0038] Alternatively, for example,a suitably protected penem can be reacted with a dialkylaminosulfur trifluoride preferably diethylaminosulfur trifluoride, usually in the presence of an inorganic base, e.g. calcium carbonate, to convert the hydroxy to fluoro.
[0039] Generally, in the process of the invention, the carboxy group of the compounds [IX(a), IX(b)], XI and XIII, and the starting penem of process D will be protected in the respective process. Thus, for instance, the alkylation reaction of process A will give a carboxy protected derivative of the respective compound of formula I which has subsequently to be deprotected. The hydroxy group of the hydroxyalkyl attached to the 3-position of the azetidinone ring of the said compounds may also, conveniently, be protected.
[0040] Suitable hydroxy protecting groups for use in the process of this invention are such groups conventionally used for such purpose in the S-lactam art and which are readily removable by procedures utilizing elemental zinc or any other conventional procedures. Preferred hydroxy protecting groups are trichloroethoxycarbonyl, dimethyltri- butylsilyl, trimethylsilyloxycarbonyl and trimethylsilyl:trimethylsilyl is a particularly preferred protecting group and is removable by treatment with a mild aqueous acid, such as aqueous acetic acid.
[0041] Suitable carboxy protecting groups are those conventionally used in the penem art and which can be removed under conventional conditions without reaction with other functional groups present on the penem molecule, for example allylic, p-nitrobenzyl and trichloroethyl. The preferred carboxy protecting group is allyl.
[0042] The removal of the protecting group from a protected carboxyl group can be carried out by conventional procedures selected according to the identity of the protecting group. For the removal of the preferred protecting group, allyl, this can in general be effected under catalytic conditions in the presence of a base, preferably by utilizing procedures described in our European Patent Application Publication No. 0013663. Thus an allyl group is preferably removed by utilizing a suitable aprotic solvent, such as tetrahydrofuran, diethyl ether or methylene chloride, with an alkali metal alkylcarboxylate, preferably potassium or sodium 2-ethylhexanoate (to give the alkali metal penem salt, preferably the sodium or potassium penem salt directly) or carboxylic acid, preferably 2-ethylhexanoic acid (to give the penem free- acid) and a mixture of a palladium compound and triphenyl phosphine as a catalyst.
[0043] If the product is a zwitterion deprotection of the allylic group requires only the catalyst and any mild neucleophile (e.g. H20 or alcohol).
[0044] Preparation of the foregoing salts and esters may be carried out according to conventional procedures for forming salts of beta-lactams such as penicillins, cephalosporins and penems. Salts can be formed upon deprotection of an allyl group as above, or for example, by treating the free acid with metal compounds such as alkali metal salts of suitable carboxylic acids, or with ammonia or a suitable organic amine, wherein preferably stoichiometric amounts or only a small-excess of the salt-forming agent is used. Acid addition salts of the compound can be obtained in the usual manner, for example by treating a compound of formula I with an acid or a suitable anion exchange reagent. Zwitterions may be formed by neutralizing salts such as acid addition salts to the isoelectric point. The esters are preparable in a manner analogous to the preparation of the corresponding esters of penicillins and cephalosporins.
[0046] The compounds may be prepared as their racemic mixtures, e.g., a 5R,6S,8R compound is produced with its enantiomer (mirror image), i.e., a 5S,6R,8S compound, in equal amounts when the starting compound is a racemic mixture. The two enantiomers may, if desired, be separated by conventional means, e.g., by fractional crystallizations of optically active salt forms, e.g., the salts derived from optically active amino compounds, e.g., (-)-brucine, or (+)- and (-)-ephedrine.
[0047] Alternatively, the compounds may be produced in optically active form by utilizing optically active starting material in the reaction procedures.
[0048] The starting materials for the procedures described above are either known in the art or can be prepared by standard methods.
[0049] The compounds of formula X in which R is loweralkyl substituted by groups such as cyano or halogen may be prepared from compounds of the formula XIII
in which R" is hydroxyloweralkyl, n and Q are as defined above and L is a hydroxy protecting group. The hydroxy of the R" group is mesylated e.g. by reaction with mesylchloride in dry pyridine at room temperature, and the mesyl group then displaced by reaction with an appropriate cyano or halogen containing reagent e.g. sodium cyanide or hydrogen fluoride. The protected oxygen can then be deprotected and displaced by or functionalized to the appropriate Z group e.g. it may be mesylated by reaction with mesylchloride as mentioned above for the R" group, or converted to halide by reaction with a hydrogen halide.
[0050] The tautomeric compound of formula IIX(a),IX(b)] can be prepared by the methods disclosed in European Patent Application No. 83111615.7.
[0051] A description of a suitable procedure is given below in which for convenience compounds of 5R,6S,8R stereochemistry and a 6-(1-hydroxyethyl substituent is produced. It will be apparent to the skilled man, however, that compounds of other stereoconfigurations and other hydroxy- alkylsubstituents at the 6-position, as well as with carboxy protecting groups other than allyl, can be prepared using the same method.
[0052] This procedure, in a preferred form, comprises:
a) reacting an azetidinome of formula XX
in which R3 is a sulfur protecting group, e.g. triphenylmethyl, with an a-substituted alkylacetate
of formula XXI
in which W is a leaving group e.g. iodo or bromo to form a compound of formula XXII
This reaction can be carried out at 150 to 30°C in the pre- sence of an acid acceptor. Preferably the reaction is conducted in acetonitrile
employing cesium carbonate or tetraalkyl ammonium hydroxide as the acid acceptor;
b) treating the compound of formula XXII with a stoi- chliometric excess of elemental
zinc in hydrochloric acid in an suitable organic solvent such as tetrahydrofuran at
15°C to 25°, to form the compound of formula XXIII
c) protecting the hydroxy group at the 5 position with a trimethylsilyl group by reaction of compound of formula XXIII with bis-trimethyl silylacetamide; the reaction suitably being carried out in a solvent such as dimethylformamide at 0°C to 30°;
d) reacting the resulting protected compound with a thiocarbonyl compound of formula
XXIV
in which Y is a leaving group such as halogen naphthyloxy or imidazolyl, generally
using the same solvent as in the preceding step at a temperature in the range 10°C
to 45°C to form the compound XXV
in which Pris trimethylsilyl and Y is as defined above;
c) treating compound XXV with an equimolar amount of a strong base such as lithium diisopropyl amide, to produce a compound [IX(a), IX(b)]; the reaction will generally be carried out in an anhydrous inert organic solvent, such as tetrahydrofuran, with the base being added to a solution of compound XXV in the solvent; typical reaction temperatures are -50°C to -100°C, and the reaction will generally be complete within 5 minutes to 24 hours.
[0053] The compounds of formula XIII can be obtained by following the procedure described in European Patent Application publication No. 58317, e.g. by reacting of a compound of the formula
in which G, n and Q are as defined above, with a reactive derivative, e.g. chloride, of an acid of the formula
in which Pg is a carboxy protecting group as defined above. This reaction is usually carried out under normal acylating conditions, namely in an inert solvent and in the presence of an organic base, preferably a tertiary amine.
[0054] Typical examples of compounds of the present invention are:
5R,6S,8R-2-[2-(imidazol-l-yl)etbylthio]-6-(1-bydroxy- etbyl)penem-3-carboxylic acid,
5R,6S,8R-2-[2-(1,2,4-1H-triazol-l-yl)etbylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid, sodium salt,
5R,6S,8R-2-[2-(1,2,3-triazol-1-yl)ethylthio]-6-(1-hydroxyethyl)penea-3-carboxylic acid,
5R,6S,8R-2-[2-(2-methyl-5-nitroinndazol-1-yl)ethylthio] -6-(1-hydroxyethyl)penen)-3-carboxylic acid,
5R, 6S, 8R-2-[2-tetrazol-1-yl)ethylthio]-6-(1-hydroxyethyl) penem-3-carboxylic acid,
5R,6S,8R-2-[2-(tetrazol-2-yl)ethylthio-6-(1-hydroxyethyl) penem-3-carboxylic acid,
5R,6S,8R-2-[1-(R,S)-methyl-2-(inddazol-1-yl)ethylthio] -6-(1-hydroxyethyl)penem-3-carboxylic acid,
PREPARATION 1
Bromoethylimidazole
[0055] A) Dissolve 10 g imidazole and 20 g ethylene carbonate in 20 ml toluene, heat at reflux for 5 hours, cool, and remove the top layer. With cooling, add 15 ml concentrated hydrochloric acid to the bottom layer, then extract the excess ethylene carbonate with chloroform. Add potassium carbonate to make basic, extract with 5 x 50 ml chloroform, dry over sodium sulfate and evaporate the solvent in vacuo. Distill under reduced pressure to obtain hydroxyethylimidazole, b.p. 134-136°C /0.5 mm.
[0056] B) Dissolve 1.1 g of hydroxyethylimidazole in 10 ml chloroform. Cool in an ice bath, add a solution of 2.28 g thionyl bromide in 5 ml chloroform and stir for 30 minutes. Stir another hour at room temperature, then pour the resultant mixture into 15 ml cold water and neutralize with sodium bicarbonate. Separate the chloroform layer and retain; extract the aqueous layer with 15 ml chloroform. Combine the chloroform solution, dry over sodium sulfate and evaporate the solvent to obtain bromoethylimidazole.
PREPARATION 1 A
Bromoethylimidazole Hydrobromide salt
[0057] Dissolve 5.2 g of hydroxyethylimidazole (preparation I, step A) in 25 ml methylene chloride. Cool in an ice bath, add 3.85 ml thionyl bromide in 10 ml methylene chloride and stir for 1 hour. Evaporate the solvent in vacuo and use the resultant residue without further purification.
PREPARATION 2
Bromoethyltriazole Hydrobromide Salt
[0058] A) Dissolve 3.2 g potassium tert-butoxide in 40 ml methanol, add 2.0 g 1,2,4-triazole and 3.6 g 2-bromoethanol and stir overnight. Evaporate the solvent in vacuo. Dissolve the residue in ethyl acetate and purify by column chromatography (silica gel, elute with methylene chloride changing to 10% methanol in methylene chloride). Combine fractions containing more polar product as shown by TLC and evaporate the solvent in vacuo to obtain hydroxyethyltriazole.
[0059] B) Stir 600 mg of the product of step A and 1.1 g thionyl bromide in 6 ml of chloroform under a nitrogen atmosphere for 1 112 hours. Evaporate the solvent in vacuo. Dry the resultant residue under high vacuum for 15 minutes to obtain the title compound.
PREPARATION 3
(2-Hydroxv)propylimidazole
[0060] Mix 6.8 g imidazole and 15.3 g propylene carbonate and heat at 140°C for 1 hour. Chromatograph the resultant residue on silica gel, eluting with methylene chloride: ethyl acetate (1:1), then with 5→ 10% methanol in methylene chloride to obtain the title compound.
PREPARATION 4
3-Hvdraxv-4- (imidazol-1-yl)butvronitrile
[0061] A) Cool to 0°C a solution of 9 g sodium imidazole in 40 ml dimethylformamide, add 13.7 g epibromohydrin in 40 ml dimethylformamide, and warm to room temperature for 30 minutes. Evaporate the solvent in vacuo and purify the resultant residue on silica gel, eluting with tetrahydrofuran, to obtain epiimidazole hydrin.
[0062] B) Dissolve 12,4 g of the product of step A in 25 ml dimethylsulfoxide, add 4.9 g sodium cyanide in 25 ml dimethylsulfoxide, and warm to 50°C. Evaporate the solvent in vacuo and purify the resultant residue on silica gel using tetrahydrofuran → 20% methanol in tetrahydo- furan to obtain the title compound.
PREPARATION 5
1-Ethoxy-1-(2-mercaptohydroxy-3-(imidazol-1-yl)propoxy) ethane
[0063]
A) Dissolve 40 g glycidol in 1 liter methylene chloride, add 40 g ethyl-vinyl-ether and cool to 2°C. Add 250 mg p-toluenesulfonic acid and warm slowly to room temperature. Evaporate the solvent in vacuo and distill the residue at 2mm Hg (b.p. 39-41°C) to obtain 1-(2,3-ethoxy- propyloxy)-l-ethoxy)-ethane.
B) Dissolve 16.6 g imidazole in 75 ml dimethylformamide, add 35.82 g of the product of step A and heat slowly to 120°C. Cool the resultant mixture to room temperature. Evaporate the solvent in vacuo, partition the resultant residue between methylene chloride and water (125 ml/ 125 ml), extract once with water, then evaporate the organic layer in vacuo to obtain l-ethoxy-l-(2-hydroxy-3-(imidazol-1-yl)propoxy)ethane.
C) To 4.0 g of the product of step B in 30 ml methylene chloride add 3.2 ml triethylamine and 1.6 ml methanesulfonyl chloride. Stir at room temperature for 1 hour, then extract the resultant mixture with water (2 x 50 ml) and evaporate the organic layer in vacuo to obtain 1- ethoxy-l-(2-methyl-sulfonyloxy-3-(imidazol-l-yl)-propoxy) ethane.
D) To 4.25 g of the product of step C in 25 ml dimethylformamide, add 5.25 g sodium thioacetate, and stir 48 hours at room temperature. Evaporate the solvent in vacuo, dissolve the resultant residue in 100 ml methylene chloride, filter and evaporate the methylene chloride in vacuo. Dissolve the residue in 100 ml ethanol, saturate with ammonia and let stand at room temperature for 1 hour. Evaporate the solvent in vacuo, partition the resultant residue between water and methylene chloride, then remove the methylene chloride in vacuo. Purify the resultant residue on silica gel, eluting with ethyl acetate:methylene chloride (1:1) to obtain the title compound
PREPARATION 6
[0064]
A) Heat together for 2 hours, at 120°C, 6.8 g imidazole and 16 g ethylene carbonate. Cool the reaction mixture and purify by chromatography using a silica gel column (100%methylene chloride → 100%ethylacetate) to give N-hydroxyethylimidazole.
B) Dissolve 10 g of N-hydroxyethylimidazole in 100 ml methylene chloride. Cool the solution to 0°C and add 1.2 equivalents of triethylamine, followed by 1.1 equivalents of methylsulfonylchloride added over 5 minutes. Warm the reaction mixture to room temperature and stir for 1 hour. Partition the resulting reaction mixture between water and methylene chloride. Collect the organic layer and remove the methylene chloride to give N-methylsulfonyloxyethylimidazole.
C) Dissolve 10 g of N-methylsulfonyloxyethylimidazole in 25 ml dimethylformamide. Add 2 equivalents of sodium thio-acetate and stir at room temperature for 48 hours. Remove the solvent in vacuo, add methylene chloride, filter and remove the methylene chloride in vacuo. Dissolve the residue in 200 ml ethanol and saturate with ammonia. Allow the solution to stand at room temperature for 1 hour. Remove the ethanol in vacuo. Purify on silica gel using 100%methylene chloride→100%ethylacetate to give N-mercaptoethylimidazole.
D) To a solution of 10 g N-mercaptoethylimidazole in 50 ml H2O and 50 ml ethanol add 1 equivalent sodium hydroxide and 10 ml of CS2. Stir the reaction
mixture for one hour to obtain a solution containing the imidazole derivative of the
formula A
E) Charge to a 250 ml flask 5 g (0.0143M) 3-(1-(2,2,2-trichloroethyloxycarbonyloxy)ethyl)-4 acetoxy -azetidin-2-one ard 50 ml methylene chloride. Add 1.5 equivalents of the imidazole derivative (formula A)from step D in aqueous ethanol to the mixture in the flask and stir the resulting mixture for 1 hour. Chromatograph the reaction mixture on silica gel to isolate 3-(1-(2,2,2-trichloroethyloxycarbonyloxy)ethyl)-4(2-(imidazol-1-yl) ethylthiocarbothioylthio)-azetidin-2-one.
F) Charge the azetidinone isolate from stept E together with 50 ml methylene chloride
to a 100 ml flask. Cool the mixture to -20°C and add 1.2 equivalents of allyloxal-
ylchloride to the mixture. Add 1.2 equivalents diisopropyl ethylamine (Münings base)
in methylene chloride over 5 minutes and stir for 45 minutes. Wash the reaction mixture
with H20 to obtain a compound having the formula B
EXAMPLE 1
(5R,65,8R)-2-[2-(Imidazol-1-yl)ethylthiol-6-[1-hydroxy ethvl)penem-3-carboxylic acid
[0065]
A) To a solution of 0.5 g of allyl (5R,6S,8R)-2-thiol-6-(l-hydroxyethyl)penem-3-carboxylate and allyl (5R,6S, 8R)-2-thione-6-(1-hydroxyethyl)penem-3-carboxylate in 10 ml tetrahydrofuran (THF), add 0.7 g brcmoethylimida- zole, followed by 2.0 ml of a 5% aqueous solution of sodium bicarbonate, and stir at room temperature for 3 hours or until thin layer chromatography (ethyl acetate/ THF, 50/50) indicates no starting material is left. Evaporate the THF in vacuo, add 10 ml water to the resultant residue and extract with 2 - 20 ml methylene chloride. Dry the organic layer over sodium sulfate and concentrate in vacuo to an oil. Purify the crude oil by column chromatography (silica gel, eluted with 5% methanol in methylene chloride)to obtain 100 mg of allyl (5R,6S,8R)-2-[2-(imidazol-1-yl)-ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylate.
B) Under argon, add 100 mg of the allyl ester product of step A) to 10 ml methylene chloride, followed by 25 mg triphenyl phosphine, 45 mg 2-ethyl hexanoic acid, and 10 mg Pd reagent. Allow the mixture to stand until the reaction is complete as shown by thin layer chromatography (5% methanol in methylene chloride as solvent). Extract the resultant product with 2 x 10 ml water, then wash the aqueous layer with 3 x 10 ml methylene chloride. Lyophilize the aqueous layer to obtain 73 mg of crude title compound.
[0066] Purify the product by reverse phase column chromatography (25 g silica gel eluted with water) to obtain 53 mg of the title compound.
NMR - (D20) = 8.65 (lH,s), 7.4 -(2H,d)), 5.3 (lH,s), 4,4 (2H,m), 4.05 (lH,m), 3.7 (lH,d), 3.3 (2H,m), 1.5 (3H,d).
EXAMPLE 1 A
(5R,6S,8R)-2-[2-(Imidazol-1-yl)ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylic acid
[0067] A) Dissolve 3.0 g of allyl(5R,6S,8R)-2-thiol-6-(hydroxyethyl)penem-3-carboxylate and allyl(5R,6S,8R)-2-thione-6-(l-hydroxyethyl)penem-3-carboxylate in 30 ml THF and 10 ml water. Add a solution of 5.12 g bromoethylimidazole hydrobromide salt (preparation 1 A) in 20 ml THF and 20 ml water, followed immediately by 3 g sodium bicarbonate in 10 ml water. Stir at room temperature for 2½ hours or until thin layer chromatography (30% ethyl acetate in methylene chloride) indicates the reaction is complete. Add 100 ml water to the resultant mixture and extract with 2 x 100 ml ethyl acetate. Dry the organic layer over sodium sulfate and concentrate in vacuo.
[0068] Purify as in Example 1 to obtain allyl(5R,6S,8R)-2-[2-(imidazol-1-yl)-ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylate.
EXAMPLE 2
(5R,6S,8R)-2-[2-(1,2,4-1H-TRIAZOL-1-YL)-ETHYLTHIO]-6-(1-HYDROXYETHYL)PENEM-3-CARBOXYLIC ACID
[0070] A) Proceed similarly to the procedure of Example 1 A, step A, first paragraph, but substitute bromoethyltriazole hydrobromide salt (preparation 2) for the bromoethylimidazole HBr salt. Then slurry in hot ethyl acetate, cool and filter to obtain ally (5R,6S, 8R)-2-[1,2,4-1H-triazol-1-yl)ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylate.
NMR-90 mHz (CD3CN) - = 8.22 (1H,s), 7.92 (1H,s), 6.3-5.6 (1H,m), 5.69 (1H,d,J-1.5Hz), 5.65-5.08 (2H,m), 4.8-4.6 (2H,m), 4.5-4.4 (2H, m), 4.3-3.9 (1H,m), 3.78 (1H,dd,J=1.5 Hz, 6Hz), 3.6-3.2 (2H,m), 1.23 (3H,d,J=6Hz)
[0071] B) Under nitrogen, stir 160 mg of the product of step A, 0.1 ml pyridine and 0.265 ml 2-ethylhexanoic acid in 6 ml acetonitrile for 1 hour. Evaporate the solvent in vacuo at 40°C or lower. Add methylene chloride and water to the resultant residue. Separate the water layer and extract the methylene chloride layer with 3 x 20 ml water. Combine the aqueous extracts and wash with methylene chloride. Evaporate the water in vacuo to obtain the title compound:
NMR-90 mHz (D2O) - = 8.5 (lH,s), 8.13 (1H,s), 5.51 (1H,d,J = 1.5 Hz), 4.7-4.5 (2H,m), 4.4-4.05 (1H,m), 3.83 (1H,dd,J = 1.5, 6Hz), 3.7-3.15 (2H,m), 1.29 (3H,d,J = 6Hz).
EXAMPLE 3
(5R,6S,8R,2(R,S))-2-(1-METHYL-2-(IMIDAZOL-1-YL)-ETHYLTHIO)-6-(1-HYDROXYETHYL)PENEM-3-CARBOXYLIC ACID
[0072] A) Dissolve 0.5 g of 2-(hydroxy)propylimidazole (Preparation 3) in 2 ml methylene chloride and add the resultant solution to a mixture of 0.8 ml trifluoromethanesulfonic anhydride and 0.83 ml diisopropylethylamine in 10 ml methylene chloride at 0°C. Stir for 30 minutes, than add the resultant mixture to a solution of 1 g of allyl(5R,6S,8R)-2-thiol-6-(l-hydroxyethyl) penem-3-carboxylic acid and allyl(5R,6S,8R)-2-thione-6-(1-hydroxyethyl)penem-3-carboxylate in 10 ml tetrahydrofuran, 10 ml water, and 0.3 g sodium bicarbonate. Stir at room temperature until thin layer chromography (methanol:methylene chloride, 1:9) indicates no starting material is left. Evaporate the solvent in vacuo and partition the resultant residue between water and methylene chloride. Dry the organic layer over magnesium sulfate and evaporate the solvent in vacuo. Purify the resultant residue using silica gel, eluting with 25% ethyl acetate/methylene chloride → 100% ethyl acetate to obtain allyl(5R,6S,8R,2(RS))-2-[1-methyl-2-(imidazol-1-yl)ethylthio]-6-(1hydroxyethyl)penem-3-carboxylate.
[0073] B) Treat the product of step A in a manner similar to that described in Example 2, step D to obtain the title compound.
EXAMPLE 4
(5R,6S.8R,2(R,S) -2-[1-CYANOMETHYL-2-( IMIDAZO-1-YL)ETFYL-THIO]-6-(1-HYDROXYETHYL)PENEM-3-CARBOXYLIC ACID
[0074] A) Treat the product of Preparation 4 in a manner similar to that described in Example 3, step A , first sentence, but substituting triethylamine for diisopropylethylamine and cooling to -78°C. Then proceed as further described in Example 3, step A, carrying out the reaction with the thiol and thione at 0°C to obtain allyl(5R,6S,8R,2(R,S)) -2-[1- cyanomethyl-2-(imidazol-1-yl)ethylthio)-6-(1-hydroxyethyl)-penem-3-carboxylate.
[0075] Alternatively, dissolve the residue of preparation 4, step B in 50 ml methylene chloride at 0°C, add 1.2 equivalents of triethylamine, 1 equivalent of methanesulfonyl chloride, and warm to room temperature for 30 minutes. Evaporate the solvent in vacuo, extract the resultant residue with tetrahydrofuran and continue with the reaction with the thiol and thione as described in Example 4, step A , above
[0076] B) Treat the product of step A in a manner similar to that described in Example 2, step B to obtain the title compound.
EXAMPLE 5
(5R,6S,8R,2(R,S))-2-(1-HYDROXYMETHYL-2-[1-IMIDAZOL-1-YL)-ETHYLTHIO]-6-(1-HYDROXYETHYL)PENEM-3-CARBOXYLIC ACID
[0077] A) Dissolve 2 g of allyl (5R,6S,8R)-2-ethylthio-6-(l-hydroxyethyl)penem-3-carboxylate in 80 ml methylene chloride at -50C, add 2 g calcium carbonate, then 1.1 g m-perbenzoic acid in 20 ml methylene chloride. After 20 minutes extract the reaction mixture with 100 ml water, separate and evaporate the organic layer to obtain allyl(5R,6S,SR)-2-ethylsulfinyl-6-(1-hydroxyethyl) penem-3-carboxylate.
[0078] B) Dissolve 500 mg of the product of step A in a mixture of 4 ml acetonitrile and 2 ml water, add 100 mg sodium bicarbonate, then 700 mg of the product of preparation 5 and let stand 1 hour. Partition the resultant mixture between methylene chloride and water, evaporate the methylene chloride and purify the resultant residue on a silica gel column using methylene chloride:tetrahydrofuran (1:1) to obtain allyl(5R,6S,8R2(R,S))-2-[1-(ethoxy -1-ethoxy)-methyl-2-(imidazol-1-yl)ethylthio]-6-(hydroxyethyl)penem-3-carboxylate.
[0079] Alternatively, react the mesylate product of preparation 5, step C, allyl(5R,6S,8R)-2-thiol-6-(l-hydroxyethyl) penem-3--carboxylate and allyl(5R,6S,8R)-2-thione-6-(1-hydroxyethyl)penem-3-carboxylate, in a manner similar to the reaction described in Example 3, step B.
[0080] C) Dissolve 174 mg of the product of step B in 10 ml of a mixture of water:tetrahydrofuran (1:1), then adjust to pH 3 with a 5% aqueous solution of p-toluenesulfonic acid. Let the mixture stand for 1.5 hours, evaporate the solvent in vacuo and partition the resultant residue between 5% aqueous sodium bicarbonate and methylene chloride. Evaporate the organic layer, redissolve the resultant residue in 10 ml methylene chloride and continue using the procedure described in Example 1, step B, to obtain the title compound.
EXAMPLE 6
(5R,6S,8R,2(R,S))-2-fl-FLUOROMETHYL-2-(IMIDAZOL-1-YL)-ETHYLTHIO]-6-(1-HYDROXYETHYL)PENEM-3-CARBOXYLIC ACID
[0081] A) Dissolve 0.100 g of the product of Example 5, step G obtained before carrying out the procedure of Example 1, step B, said product being allyl(5R,6S,8R(2R,S))-2-[1-hydroxymethyl-2-(imidazol-1-yl)-ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylate, together with 0.05 g of calcium carbonate in 5 ml of methylene chloride at -78oC. Add 0.043 g of diethylaminosulfur trifluoride and stir for 30 minutes. Dilute with ethyl acetate, then stir with water for 5 minutes at O°C. Separate the organic layer, wash with water and evaporate the solvent. Chromatograph the resultant residue on silica gel, eluting with methylene chloride:ethyl acetate to obtain allyl(5R,6S,8R,2(R,S))-2-[l-fluoro-methyl-2-(imidazol-1-yl)ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylate.
[0082] B) Treat the product of step A in a manner similar to that described in Example 1, step B, to obtain the title compound.
EXAMPLE 7
(5R,6S,8R.2(R,S))-2-[2-HYDROXY-3-(IMIDAZOL-1-YL) PROPYLTHIO]-6-(1-HYDROXYETHYL)PENEM-3-CARBOXYLIC ACID
[0083] A) Slowly combine epiimidazolohydrin as prepared in Preparation 4, step A with 600 mg of allyl(5R,6S,8R)-2-thiol-6-(l-hydroxyethyl)penem-3-carboxylate and allyl (5R,6S,8R)-2-thione-6-(1-hydroxyethyl)penem-3-carboxylate in 2 ml dimethylformamide and stir until thin layer chromatography (on silica gel elute with methanol: methylene chloride (1:9)) shows no more thione present. Partition the resultant solution between water and methylene chloride, evaporate the organic layer and purify the resultant residue on a silica gel column, eluting with 5 → 10% ethanol in methylene chloride.
[0084] B) Treat the product of step A in a manner similar to that described in Example 1, step B, to obtain the title compound.
EXAMPLE 8
5R,6S,8R-2-[2-(Imidazol-1-yl)ethylthio]-6-(1-hgdroxyethyl) penem-3-carboxylic acid
[0085] A) Charge 5 g of compound of formula B (preparation 6) together with 50 ml distilled methylene chloride. Heat to reflux and add over 2 hours two equivalents of triethyl phosphite. Reflux for 4 hours by which time cyclisation is complete. Isolate the cyclised product by chromatography on silica gel to obtain a compound having the formula C
[0087] B) Dissolve 1.6 g of the compound of formula C in a mixture consisting of 1.5 ml acetic acid, 1.5 ml water and 15 ml tetrahydrofuran. Add 1.25 g zinc dust and stir the mixture at 0° to 5°C. After 1 hour filter, wash the filtrate with saturated sodium bicarbonate solution. Dry the filtrate over magnesium sulfate, filter and evaporate to a residue.Crystallize the residue from ethylether:methylene chloride to obtain compound of formula D
[0089] By following the procedures outlined in the above examples, and conventional procedures for salt and ester formation, the following compounds of this invention may be prepared:
[0090] Compounds of the formula
wherein W is
*) ketoform and sodium and potassium salts or pharmaceutically acceptable esters thereof.
[0091] Compounds of the formula
wherein X is as defined above and Y is
and sodium and potassium salts and pharmaceutically acceptable esters thereof.
[0092] In the following examples the Active Ingredient is 5R,6S, 8R-2-[2-(imidazol-1-yl)ethylthio)-6-(1-hydroxyethyl) penem-3-carboxylic acid or an equivalent amount of any of its pharmaceutically acceptable salts and esters, or any of the other compounds of formula 1, mentioned above, or their salts or esters.
EXAMPLE 9
Iniectable Solution
Method of Manufacture
[0094]
1. Dissolve the parabens in a portion (85% of the final volume) of the water for injection at 65 - 70°C.
2. Cool to 25 to 350C. Charge and dissolve the sodium bisulfite, disodium edetate and sodium sulfate.
3. Charge and dissolve the active ingredient.
4. Bring the solution to final volume by adding water for injection.
5. Filter the solution through 0.22 µ membrane and fill into appropriate containers.
6. Terminally sterilize the units by autoclaving.
EXAMPLE 10
Injectable Powder: (per vial)
wherein G is hydroxyloweralkyl;
Q is the group
wherein
each X is
or =N-, with the proviso that at least
one X is
R is hydrogen, loweralkyl, aminoloweralkyl, mono- and di-loweralkylaminoloweralkyl, carboxyloweralkyl, sulfoalkyl, hydroxyalkyl, cyano, hydroxy, amino, mono- and di-loweralkylamino, alkylsulfonate, sulfamyl, halogeno, hydroxyliiuinoloweralkyl, loweralkoxyisnino-, loweralkyl, carboxy, carbamyl, mono- or di-loweralkylcarbamyl, nitro, carbamyloxy, ureidoloweralkyl, or carbamyl- hydrazoloweralkyl; or two R croups, together with the carbon atoms to which they are attached, form a fused aromatic ring;
R1 is hydrogen, loweralkyl, carboxy, carbamyl, cyano, hydroxy, amino,loweralkylthio,
fluoro, loweralkoxy, loweralkanoyloxy, or loweralkyl substituted by imida- zoly (which
may be substituted by a group defined by R or by ureido), hydroxy, cyano, halogen,
loweralkoxy, carbamyloxy, carboxy, carbamyl, loweralkylcarbonyl, sulfo, sulfamyl,
loweralkylsulfonyl, loweralkoxysulfo- nyl,loweralkoxycarbonyl, hydroxyloweralkylcarbonyl
or hydroxyloweralkylsulfonyl, with the proviso that when R1 is attached to a carbon atom adjacent either to the sulphur atom connected to the
2-position of the penem ring or the nitrogen atcm by which the group Q is connected
to the side chain
then such R1 cannot be hydroxy, amino or fluoro;
n is 1 to 4;
and
the pharmaceutically acceptable salts and esters thereof, in racemic or optically
active form.
5R,6S,8R-2-[2-(imidazol-1-yl)ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylic acid,
5R,6S,8R-2-[2-(1,2,4-1H-triazol-1-yl)ethylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid,
5R,6S,8R-2-[2-(1,2,3-triazol-1-yl)ethylthio]-6-(1-hydroxyethyl)penem-3-carboxylic acid,
5R,6S,8R-2-[2-(2-methyl-5-nitroimicazol-1-yl)ethylthio] -6-(1-hydroxyethyl)penem-3-carboxylic acid,
5R,6S,8R-2-[2-tetrazol-1-yl)ethylthlo]-6-(1-hydroxyethyl) penem-3-carboxylic acid,
5R,6S,8R-2-[2-(tetrazol-2-yl)ethylthio-6-(l-hydroxyethyl) penem-3-carboxylic acid,
5R,6S,8R-2-[1-(R,S)-methyl-2-(imidazol-1-yl)ethylthio] -6-(1-hydroxyethyl)penem-3-carboxylic acid,
or a pharmaceutically acceptable salt or ester of any one of the foregoing compounds.
A) a compound of formula [IX(a), IX(b)]
in which G is as defined above, is transformed into a compound of formula I by introducing
the group
(in which Q, n and R1 are as previously defined) by known conventional methods;
B) Reaction of a compound of the general formula XI
in which G is as defined above and R5 is an organic group, with a compound of general formula XII
in which Q, n and R' are as previously defined, or with a reactive derivative thereof,
wherein the group R5 is different from the group
by which it is replaced,
C) intramolecular cyclisation of a compound having the general formula XIII
in which G, n, R1 and Q are as defined above and Z is oxygen or sulphur, in the presence of a trivalent
organophosphorous compound;
D) for the preparation of a compound of formula I in which at least one R1 is cyano or fluoro, converting at least one hydroxyl group representing R1 in an compound of formula I into the cyano or fluoro group;
wherein in the processes A, B, C or D, any functional groups are protected if necessary
or desired,
the process A, B, C, or D, being followed by removal of any protecting groups, before or after any desired separation of a stereoisomer, and isolation of the resulting penem compound of formula I as the free acid, pharmaceutically acceptable salt or pharmaceutically acceptable ester.
wherein G is hydroxyloweralkyl,
Q is the group
wherein
each X is
or =N-, with the proviso that at least
one X is
R is hydrogen, loweralkyl, aminoloweralkyl, mono- and di-loweralkylaminoloweralkyl, carboxyloweralkyl, sulfoalkyl, hydroxyalkyl, cyano, hydroxy, amino, mono- and di-loweralkylamino, alkylsulfonate, sulfamyl, halogeno, hydraxylilninoloweralkyl, loweralkoxyimino-, loweralkyl, carboxy, carbamyl, mono- or di-loweralkylcarbamyl, nitro, carbamyloxy, ureidoloweralkyl, or carbamyl- hydrazoloweralkyl; or two R groups, together with the carbon atoms to which they are attached, form a fused aromatic ring;
R1 is hydrogen, loweralkyl, carboxy, carbamyl, cyano, hydroxy, amino,loweralkylthio,
fluoro, loweralkoxy, loweralkanoyloxy, or loweralkyl substituted by imida- zoly (which
may be substituted by a group defined by R or by ureido), hydroxy, cyano, halogen,
loweralkoxy, carbamyloxy, carboxy, carbamyl, loweralkylcarbonyl, sulfo, sulfamyl,
loweralkylsulfonyl, loweralkoxysulfo- nyl,loweralkoxycarbonyl, hydroxyloweralkylcarbonyl
or hydroxyloweralkylsulfonyl, with the proviso that when R1 is attached to a carbon atom adjacent either to the sulphur atom connected to the
2-position of the penem ring or the nitrogen atom by which the group Q is connected
to the side chain
then such R1 cannot be hydroxy, amino or fluoro;
n is 1 to 4;
and
the pharmaceutically acceptable salts and esters thereof, in racemic or optically
active form, characterized in that:
A) a compound of formula [IX(a) , IX(b)]
in which G is as defined above, is transformed into a compound of formula I by introducing
the group
(in which Q, n and, R1 are as previously defined) by known conventional methods;
B) Reaction of a compound of the general formula XI
in which G is as defined above and P5 i.s an organic group, with a compound of general formula XII
in which Q, n and R' are as previously defined, or with a reactive derivative thereof,
wherein the group R5 is different from the group
by which it is replaced,
C) intramolecular cyclisation of a compound having the general formula XIII
in which G, n, R1 and Q are as defined above and Z is oxygen or sulphur, in the presence of a trivalent
organophosphorous compound;
D) for the preparation of a compound of formula I in which at least one R1 is cyano or fluoro, converting at least one hydrcxyl group representing R1 in an compound of formula I into the cyano or fluoro group;
wherein in the processes A, B, C or D, any functional groups are protected if necessary
or desired,
the process A, B, C, or D, being followed by removal of any protecting groups, before or after any desired separation of a stereoisomer, and isolation of the resulting penem compound of formula I as the free acid, pharmaceutically acceptable salt or pharmaceutically acceptable ester.
5R,6S,8R-2-[2-(imidazol-1-yl-)ethylthio[-6-(1-hydroxyethyl)penem-3-carboxylic acid,
5R,6S,8R-2-[2-(1,2,4-1H-triazol-1-yl)ethylthio)-6-(hydroxyethyl)-penem-3-carboxylic acid,
5R,6S,8R-2-[2-(1,2,3-triazol-1-yl)ethylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid,
5R,6S,8R-2-[2-(2-methyl-5-nitroimidazol-1-yl)ethylthio] -6-(1-hydroxyethyl)penem-3-carboxylic acid,
5R, 6S, 8R-2-[2 -(etrazol-1-yl)ethylthio] -6-(1-hydroxyethyl) penem-3-earboxylic acid,
5R,6S,8R-2-[2-(tetrazol-2-yl)ethylthio-6-(1-hydroxyethyl) penem-3-carboxylic acid,
5R,6S,8R-2-[1-(R,S)-methyl-2-(imidazol-1-yl)ethylthio) -6-(1-hyd.roxyethyl)penem-3-carboxylic acid,
or a pharmaceutically acceptable salt or ester of any one of the foregoing compounds.